Frontiers in molecular medicine最新文献

{"title":"Elaborating the potential of Artficial Intelligence in automated CAR-T cell manufacturing","authors":"Niklas Bäckel, Simon Hort, Tamás Kis, David F. Nettleton, Joseph R. Egan, John J. L. Jacobs, Dennis Grunert, Robert H. Schmitt","doi":"10.3389/fmmed.2023.1250508","DOIUrl":"https://doi.org/10.3389/fmmed.2023.1250508","url":null,"abstract":"This paper discusses the challenges of producing CAR-T cells for cancer treatment and the potential for Artificial Intelligence (AI) for its improvement. CAR-T cell therapy was approved in 2018 as the first Advanced Therapy Medicinal Product (ATMP) for treating acute leukemia and lymphoma. ATMPs are cell- and gene-based therapies that show great promise for treating various cancers and hereditary diseases. While some new ATMPs have been approved, ongoing clinical trials are expected to lead to the approval of many more. However, the production of CAR-T cells presents a significant challenge due to the high costs associated with the manufacturing process, making the therapy very expensive (approx. $400,000). Furthermore, autologous CAR-T therapy is limited to a make-to-order approach, which makes scaling economical production difficult. First attempts are being made to automate this multi-step manufacturing process, which will not only directly reduce the high manufacturing costs but will also enable comprehensive data collection. AI technologies have the ability to analyze this data and convert it into knowledge and insights. In order to exploit these opportunities, this paper analyses the data potential in the automated CAR-T production process and creates a mapping to the capabilities of AI applications. The paper explores the possible use of AI in analyzing the data generated during the automated process and its capabilities to further improve the efficiency and cost-effectiveness of CAR-T cell production.","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"144 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136238351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astrocytes in stroke-induced neurodegeneration: a timeline.","authors":"Eileen Collyer, Elena Blanco-Suarez","doi":"10.3389/fmmed.2023.1240862","DOIUrl":"10.3389/fmmed.2023.1240862","url":null,"abstract":"<p><p>Stroke is a condition characterized by sudden deprivation of blood flow to a brain region and defined by different post-injury phases, which involve various molecular and cellular cascades. At an early stage during the acute phase, fast initial cell death occurs, followed by inflammation and scarring. This is followed by a sub-acute or recovery phase when endogenous plasticity mechanisms may promote spontaneous recovery, depending on various factors that are yet to be completely understood. At later time points, stroke leads to greater neurodegeneration compared to healthy controls in both clinical and preclinical studies, this is evident during the chronic phase when recovery slows down and neurodegenerative signatures appear. Astrocytes have been studied in the context of ischemic stroke due to their role in glutamate re-uptake, as components of the neurovascular unit, as building blocks of the glial scar, and synaptic plasticity regulators. All these roles render astrocytes interesting, yet understudied players in the context of stroke-induced neurodegeneration. With this review, we provide a summary of previous research, highlight astrocytes as potential therapeutic targets, and formulate questions about the role of astrocytes in the mechanisms during the acute, sub-acute, and chronic post-stroke phases that may lead to neurorestoration or neurodegeneration.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1240862"},"PeriodicalIF":0.0,"publicationDate":"2023-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285566/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42901964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How can we use stem cell-derived cardiomyocytes to understand the involvement of energetic metabolism in alterations of cardiac function?","authors":"Sabine Rebs, Katrin Streckfuss-Bömeke","doi":"10.3389/fmmed.2023.1222986","DOIUrl":"10.3389/fmmed.2023.1222986","url":null,"abstract":"<p><p>Mutations in the mitochondrial-DNA or mitochondria related nuclear-encoded-DNA lead to various multisystemic disorders collectively termed mitochondrial diseases. One in three cases of mitochondrial disease affects the heart muscle, which is called mitochondrial cardiomyopathy (MCM) and is associated with hypertrophic, dilated, and noncompact cardiomyopathy. The heart is an organ with high energy demand, and mitochondria occupy 30%-40% of its cardiomyocyte-cell volume. Mitochondrial dysfunction leads to energy depletion and has detrimental effects on cardiac performance. However, disease development and progression in the context of mitochondrial and nuclear DNA mutations, remains incompletely understood. The system of induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CM) is an excellent platform to study MCM since the unique genetic identity to their donors enables a robust recapitulation of the predicted phenotypes in a dish on a patient-specific level. Here, we focus on recent insights into MCM studied by patient-specific iPSC-CM and further discuss research gaps and advances in metabolic maturation of iPSC-CM, which is crucial for the study of mitochondrial dysfunction and to develop novel therapeutic strategies.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1222986"},"PeriodicalIF":0.0,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285589/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42102278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A method for temporal-spatial multivariate genomic analysis of acute wound healing via tissue stratification: a porcine negative pressure therapy pilot study.","authors":"Jacob G Hodge, Sumedha Gunewardena, Richard A Korentager, David S Zamierowski, Jennifer L Robinson, Adam J Mellott","doi":"10.3389/fmmed.2023.1195822","DOIUrl":"10.3389/fmmed.2023.1195822","url":null,"abstract":"<p><p><b>Introduction:</b> Wound therapies are capable of modulating the complex molecular signaling profile of tissue regeneration. However traditional, bulk tissue analysis results in nonspecific expressional profiles and diluted signaling that lacks temporal-spatial information. <b>Methods:</b> An acute incisional porcine wound model was developed in the context of negative pressure wound therapy (NPWT). Dressing materials were inserted into wounds with or without NPWT exposure and evaluated over 8-hours. Upon wound explantation, tissue was stratified and dissected into the epidermis, dermis, or subcutaneous layer, or left undissected as a bulk sample and all groups processed for RNAseq. RNAseq of stratified layers provided spatial localization of expressional changes within defined tissue regions, including angiogenesis, inflammation, and matrix remodeling. <b>Results:</b> Different expressional profiles were observed between individual tissue layers relative to each other within a single wound group and between each individual layer relative to bulk analysis. Tissue stratification identified unique differentially expressed genes within specific layers of tissue that were hidden during bulk analysis, as well as amplification of weak signals and/or inversion of signaling between two layers of the same wound, suggesting that two layers of skin can cancel out signaling within bulk analytical approaches. <b>Discussion:</b> The unique wound stratification and spatial RNAseq approach in this study provides a new methodology to observe expressional patterns more precisely within tissue that may have otherwise not been detectable. Together these experimental data offer novel insight into early expressional patterns and genomic profiles, within and between tissue layers, in wound healing pathways that could potentially help guide clinical decisions and improve wound outcomes.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1195822"},"PeriodicalIF":0.0,"publicationDate":"2023-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47534691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial calcium signaling and redox homeostasis in cardiac health and disease.","authors":"Tudor-Alexandru Popoiu, Christoph Maack, Edoardo Bertero","doi":"10.3389/fmmed.2023.1235188","DOIUrl":"10.3389/fmmed.2023.1235188","url":null,"abstract":"<p><p>The energy demand of cardiomyocytes changes continuously in response to variations in cardiac workload. Cardiac excitation-contraction coupling is fueled primarily by adenosine triphosphate (ATP) production by oxidative phosphorylation in mitochondria. The rate of mitochondrial oxidative metabolism is matched to the rate of ATP consumption in the cytosol by the parallel activation of oxidative phosphorylation by calcium (Ca²⁺) and adenosine diphosphate (ADP). During cardiac workload transitions, Ca²⁺ accumulates in the mitochondrial matrix, where it stimulates the activity of the tricarboxylic acid cycle. In this review, we describe how mitochondria internalize and extrude Ca²⁺, the relevance of this process for ATP production and redox homeostasis in the healthy heart, and how derangements in ion handling cause mitochondrial and cardiomyocyte dysfunction in heart failure.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"1 1","pages":"1235188"},"PeriodicalIF":0.0,"publicationDate":"2023-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285591/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42058449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Heart valve diseases: from molecular mechanisms to clinical implications.","authors":"Jaime Ibarrola, Natalia Lopez-Andres","doi":"10.3389/fmmed.2023.1260912","DOIUrl":"10.3389/fmmed.2023.1260912","url":null,"abstract":"","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1260912"},"PeriodicalIF":0.0,"publicationDate":"2023-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285579/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45869084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Whole genome sequencing for metastatic mutational burden in extraskeletal myxoid chondrosarcoma.","authors":"Trudy Zou, Rahil Sethi, Jiefei Wang, Gungor Budak, Uma Chandran, Ivy John, Rebecca Watters, Kurt Weiss","doi":"10.3389/fmmed.2023.1152550","DOIUrl":"10.3389/fmmed.2023.1152550","url":null,"abstract":"<p><p>Extraskeletal myxoid chondrosarcoma (EMC) is an ultra-rare cancer that makes up less than 3% of all soft tissue sarcomas. It most often arises in the soft tissues of the proximal limbs and has a higher incidence in males. Though EMC has a good prognosis, it has an indolent course with high rates of local recurrence as well as metastasis to the lungs. EMC is characterized in 70% of cases by an EWS1-NR4A3 translocation, leading to constitutive expression of NR4A3. Structural variants (SVs) in EMC, especially large-scale genomic alterations, have not been well studied and studies are severely limited by sample size. In this study, we describe Whole Genome Sequencing (WGS) of a rare case of matched EMC primary tumor, lung metastasis, and pelvic metastasis to identify genomic alterations. We examined somatic variants, copy number variants (CNVs), and larger scale SVs such as translocations and breakend points. While the primary tumor and lung metastasis had similar somatic variations and CNVs, the pelvic metastasis had more unique SVs with especially increased mutational burden of SVs in chromosome 2. This suggests that different molecular drivers appear in more advanced, relapsing EMC compared with the primary tumor and early lung metastasis. Genomic studies such as ours may identify novel molecular complexities in rare cancers that may be leveraged for therapeutic strategies and precision medicine.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1152550"},"PeriodicalIF":0.0,"publicationDate":"2023-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285543/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42081836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: CAR T-cells: novel therapeutic approaches in the new era of cancer immunotherapy.","authors":"Alice Turdo, Costanza Maria Cristiani, Niels Schaft","doi":"10.3389/fmmed.2023.1239013","DOIUrl":"10.3389/fmmed.2023.1239013","url":null,"abstract":"","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1239013"},"PeriodicalIF":0.0,"publicationDate":"2023-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285554/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43868769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Biomarkers to evaluate rare diseases.","authors":"Bridget E Bax, Dario Pacitti","doi":"10.3389/fmmed.2023.1237089","DOIUrl":"10.3389/fmmed.2023.1237089","url":null,"abstract":"","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1237089"},"PeriodicalIF":0.0,"publicationDate":"2023-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285610/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49507578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interactions between astrocytes and extracellular matrix structures contribute to neuroinflammation-associated epilepsy pathology.","authors":"AnnaLin M Woo, Harald Sontheimer","doi":"10.3389/fmmed.2023.1198021","DOIUrl":"10.3389/fmmed.2023.1198021","url":null,"abstract":"<p><p>Often considered the \"housekeeping\" cells of the brain, astrocytes have of late been rising to the forefront of neurodegenerative disorder research. Identified as crucial components of a healthy brain, it is undeniable that when astrocytes are dysfunctional, the entire brain is thrown into disarray. We offer epilepsy as a well-studied neurological disorder in which there is clear evidence of astrocyte contribution to diseases as evidenced across several different disease models, including mouse models of hippocampal sclerosis, trauma associated epilepsy, glioma-associated epilepsy, and beta-1 integrin knockout astrogliosis. In this review we suggest that astrocyte-driven neuroinflammation, which plays a large role in the pathology of epilepsy, is at least partially modulated by interactions with perineuronal nets (PNNs), highly structured formations of the extracellular matrix (ECM). These matrix structures affect synaptic placement, but also intrinsic neuronal properties such as membrane capacitance, as well as ion buffering in their immediate milieu all of which alters neuronal excitability. We propose that the interactions between PNNs and astrocytes contribute to the disease progression of epilepsy vis a vis neuroinflammation. Further investigation and alteration of these interactions to reduce the resultant neuroinflammation may serve as a potential therapeutic target that provides an alternative to the standard anti-seizure medications from which patients are so frequently unable to benefit.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":" ","pages":"1198021"},"PeriodicalIF":0.0,"publicationDate":"2023-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285605/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44271033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}